Increased Survivin Expression Confers Chemoresistance to Tumor-Associated Endothelial Cells

Jenilyn J. Virrey^*, Shengxi Guan, Wei Li, Axel H. Schönthal, Thomas C. Chen^*¶ and Florence M. Hofman^*

From the Departments of Pathology,^* Biochemistry, Dermatology, Molecular Microbiology and Immunology, and Neurosurgery,^¶ University of Southern California, Keck School of Medicine, Los Angeles, California

Growing evidence suggests that survivin, a member of the inhibitorof apoptosis gene family, is responsible for drug resistancein cancer cells, yet little is known about its role in the endothelialcells of the tumor vasculature. We have previously reportedthat tumor-associated endothelial cells derived from gliomas(TuBECs) are resistant to anticancer chemotherapy whereas normalbrain endothelial cells (BECs) are sensitive. The focus of thisstudy is to investigate the mechanism behind this chemoresistance.Here we show that survivin is constitutively overexpressed inthe glioma vasculature but not in the blood vessels of normalbrain. To determine whether survivin contributes to TuBEC chemoresistance,we used a lentiviral siRNA system or the drug roscovitine todown-regulate survivin expression. Reduced levels of survivinsensitized TuBECs to the chemotherapeutic agents VP-16, paclitaxel,thapsigargin, and temozolomide. This cell death was mediatedthrough caspases 7 and 4. Conversely, forced expression of survivinin BECs was protective against drug cytotoxicity. These datasuggest that overexpression of survivin in endothelial cellsserves as a protective mechanism that defends the vasculaturefrom drug cytotoxicity. Our studies demonstrate that targetingsurvivin may be an effective approach to chemosensitizationand anti-vascular therapy for brain tumors.